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<p>Re-administration of adeno-associated virus (AAV)-mediated gene therapy remains challenging due to neutralizing antibodies (NAbs) induced by the initial dose. We previously conducted a single-arm trial showing that single-dose administration of AAV-hOTOF gene therapy in individuals with <i>OTOF</i>-related deafness is safe and leads to hearing improvements. Here we initially demonstrate that AAV1-hOTOF re-administration to the contralateral ear in <i>Otof</i><sup><i>−/−</i></sup> mice with peak serum NAb titers successfully rescued hearing with limited immune activation. After a protocol amendment of our trial, four patients (aged 2.2–3.4 years) with pre-existing NAbs (titers 1:135–1:3,645), who had previously received a single dose of the gene therapy, were enrolled to receive a second dose in the contralateral ear, as part of the ongoing trial, with a follow-up ranging from 26 weeks to 52 weeks. The primary endpoint was the occurrence of dose-limiting toxicities at 6 weeks and secondary endpoints included safety and auditory function. No dose-limiting toxicity occurred within 6 weeks. In the secondary outcomes, the 26-week average auditory brainstem response threshold in the second treated ear improved from &gt;95 dB at baseline to 43 dB, 63 dB, 80 dB and 53 dB in patients 1–4, respectively. Safety assessment showed that all adverse events were grade 1–2, except one grade 3 decreased neutrophil count; no serious adverse events occurred. These data provide preliminary insights on the safety and efficacy of re-administration of AAV1-hOTOF gene therapy in patients with congenital deafness. Longer follow-up and larger cohorts are needed to establish the safety and efficacy of repeated administration of gene therapies. Trial registration no.: <a href="https://www.chictr.org.cn/showproj.html?proj=194989">ChiCTR2200063181</a>.</p>

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Re-administration of AAV-mediated gene therapy for OTOF-related deafness: a single-arm trial

  • 期刊论文

  • 发表日期：

    2026年6月26日

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  • Xintai Fan,
  • Longlong Zhang,
  • Ziwen Gao,
  • Lei Han,
  • Ping Yang,
  • Daqi Wang,
  • Hongbing Yu,
  • Qi Cao,
  • Luoying Jiang,
  • Xiaoyun Chen,
  • Xin Zhang,
  • Xiaoting Cheng,
  • Liheng Chen,
  • Jiake Zhong,
  • Jun Lv,
  • Wei Wang,
  • Liling Dai,
  • Ziyi Zhou,
  • Linjie Shi,
  • Yuxin Chen,
  • Biyun Zhu,
  • Shaowei Hu,
  • Honghai Tang,
  • Zheng-Yi Chen,
  • Wuqing Wang,
  • Bing Chen,
  • Huawei Li,
  • Yilai Shu

摘要

Re-administration of adeno-associated virus (AAV)-mediated gene therapy remains challenging due to neutralizing antibodies (NAbs) induced by the initial dose. We previously conducted a single-arm trial showing that single-dose administration of AAV-hOTOF gene therapy in individuals with OTOF-related deafness is safe and leads to hearing improvements. Here we initially demonstrate that AAV1-hOTOF re-administration to the contralateral ear in Otof−/− mice with peak serum NAb titers successfully rescued hearing with limited immune activation. After a protocol amendment of our trial, four patients (aged 2.2–3.4 years) with pre-existing NAbs (titers 1:135–1:3,645), who had previously received a single dose of the gene therapy, were enrolled to receive a second dose in the contralateral ear, as part of the ongoing trial, with a follow-up ranging from 26 weeks to 52 weeks. The primary endpoint was the occurrence of dose-limiting toxicities at 6 weeks and secondary endpoints included safety and auditory function. No dose-limiting toxicity occurred within 6 weeks. In the secondary outcomes, the 26-week average auditory brainstem response threshold in the second treated ear improved from >95 dB at baseline to 43 dB, 63 dB, 80 dB and 53 dB in patients 1–4, respectively. Safety assessment showed that all adverse events were grade 1–2, except one grade 3 decreased neutrophil count; no serious adverse events occurred. These data provide preliminary insights on the safety and efficacy of re-administration of AAV1-hOTOF gene therapy in patients with congenital deafness. Longer follow-up and larger cohorts are needed to establish the safety and efficacy of repeated administration of gene therapies. Trial registration no.: ChiCTR2200063181.